Genetic Variant SLC22A5:p.Ser93Ser (chr5-132370251-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_003060.4(SLC22A5):c.279G>C(p.Ser93Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,578,882 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S93S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00074 ( 1 hom. )

Consequence

SLC22A5
NM_003060.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -1.68

Publications

3 publications found

Variant links:

Genes affected

SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

SLC22A5 links:

MIR3936HG (HGNC:40538): (MIR3936 host gene)

MIR3936HG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 5-132370251-G-C is Benign according to our data. Variant chr5-132370251-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460406.

BP7

Synonymous conserved (PhyloP=-1.68 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003060.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	NM_003060.4	MANE Select	c.279G>C	p.Ser93Ser	synonymous	Exon 1 of 10	NP_003051.1
	SLC22A5	NM_001308122.2		c.279G>C	p.Ser93Ser	synonymous	Exon 1 of 11	NP_001295051.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.279G>C	p.Ser93Ser	synonymous	Exon 1 of 10	ENSP00000245407.3
SLC22A5	ENST00000435065.7	TSL:1	c.279G>C	p.Ser93Ser	synonymous	Exon 1 of 11	ENSP00000402760.2
SLC22A5	ENST00000448810.6	TSL:1	n.279G>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000401860.2

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000600

AC:

109

AN:

181690

AF XY:

0.000655

show subpopulations

Gnomad AFR exome

AF:

0.000109

Gnomad AMR exome

AF:

0.000363

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000204

GnomAD4 exome

AF:

0.000744

AC:

1062

AN:

1426560

Hom.:

Cov.:

AF XY:

0.000778

AC XY:

550

AN XY:

706612

show subpopulations

African (AFR)

AF:

0.000184

AC:

AN:

32568

American (AMR)

AF:

0.000284

AC:

AN:

38680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25618

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37396

South Asian (SAS)

AF:

0.000899

AC:

AN:

82276

European-Finnish (FIN)

AF:

0.0000203

AC:

AN:

49256

Middle Eastern (MID)

AF:

0.000183

AC:

AN:

5466

European-Non Finnish (NFE)

AF:

0.000854

AC:

936

AN:

1096180

Other (OTH)

AF:

0.000541

AC:

AN:

59120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

149

224

298

373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152322

Hom.:

Cov.:

AF XY:

0.000738

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41592

American (AMR)

AF:

0.000392

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000670

Hom.:

Bravo

AF:

0.000945

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal carnitine transport defect (5)

not provided (2)

Decreased circulating carnitine concentration (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.1

(source)

DANN

Benign

0.85

PhyloP100

-1.7

PromoterAI

-0.0049

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over